BRPI0807023A2 - THIAZOL COMPOUND AS A PPARD BINDER AND PHARMACEUTICAL, COSMETIC, AND HEALTHY PRODUCT - Google Patents

Description

"TIAZOLE COMPOUND AS A PPAROT BINDER AND PHARMACEUTICAL, COSMETIC, AND HEALTHY FOOD PRODUCT".

Technique Field

The present invention relates to the thiazole compound represented by

Formula 1 as a PPAR? (Peroxisome Proliferator Activated Receptor δ) ligand that can be used to treat obesity, hyperlipidemia, arteriosclerosis, diabetes, dementia, Alzheimer's and Parkinson's disease and used for muscle strengthening or memory and a composition

io pharmaceutical, cosmetic composition, healthy food, healthy drink, food additive and animal feed containing it.

[Formula 1]

15

Background Art

Among the nuclear receptors, it is known that PPAR (Peroxisome Proliferator Activated Receptor) has three subtypes, PPARa, PPARy and PPARÔ (Nature, 1990, 347, pp. 645-650, Proc. NatL Acad. ScL USA, 1994, 91, 20 pp. 7335-7359). PPARa, PPARy and PPARô have tissue specific functions in vivo and different expression regions. PPARα is expressed primarily in the heart, kidney, skeletal muscles and large intestine in humans (Mol. Pharmacol. 1998, 53, pp. 14-22, ToxicoL Lett. 1999, 110, pp. 119-127, J. Biol. Chem. 1998, 273, pp. 16710-16714) and is involved in the peroxisome β-oxidation and mitochondria {Biol. CelL 1993, 77, p. 67-76, J. Biol. Chem. 1997, 272, p. 27307-27312). PPARy is expressed in skeletal muscle at a low level, but is mainly expressed in adipose tissue to induce differentiation between adipocytes and store energy in the form of fat and is involved in homeostatic insulin and glucose regulation (Moll. Cell. 1999, 4, pp. 585-594, pp. 597-609, pp. 611-617). PPARô is evolutionarily preserved in mammals that include humans and vertebrates, including rodents and sea squid. Previous studies have confirmed that PPAR? Plays an important role in reproductive cell expression (Genes Dev. 1999, 13, pp. 1561-1574) and has physiological functions of differentiating neuronal cells (J. Chem. Neuroanat.

2000, 19, p. 225-232) in the central nervous system (CNS) and wound healing with anti-inflammatory effect (Genes Dev. 2001, 15, pp. 3263-3277, Proc. Natl. Acad. Sci. USA 2003, 100, pp. 6295 -6296). Recent studies have also confirmed that PPARô is involved in adipocyte differentiation and lipid metabolism {Proc. Natl. Acad. Know. U.S.A. 2002, 99, p. 303-308, Mol. Cell. Biol. 2000, 20, p. 5119-5128). PPARÔ activates, for example, the expression of the major gene involved in β-oxidation in catabolism of fatty acids and uncoupling proteins (UCPs), the gene involved in energy metabolism, which has the effect of increasing obesity QNature 2000, 406, pages 415-418, Cell 2003, 113, p. 159-170). Activation of PPARô increases HDL (High Density Lipoprotein) level, improves type 2 diabetes without weight changes {Proc. Natl. Acad. Know. U.S.A. 2001, 98, p. 5306-5311, 2003, 100, p. 15924-15929, 2006, 103, p. 3444-3449) and favors the treatment of atherosclerosis by inhibiting the atherosclerosis-associated gene 20 (Science, 2003, 302, pp. 453-457). PPAR? Ligand can therefore be developed as a drug for the treatment of metabolic diseases such as obesity, diabetes, hyperlipidemia and arteriosclerosis.

PPARô regulates mitochondria biosynthesis. When PPARô was artificially overexpressed in rat muscles, mitochondrial biosynthesis 25 increased and Type I muscle fiber increased significantly, in addition to increased fatty acid β oxidase. Constant driving time and distance increased, therefore, by 67% and 92%, respectively, compared to wild type mice (PLoS Biology, 2004, 2: e294). Increased mitochondrial biosynthesis has a positive effect on improving brain functions. 30 If mitochondria in brain cells are destroyed by oxidative stress, memory is significantly reduced {Proc. Natl. Acad. Know. U.S.A. 2002, 99, p. 2356-2361). Dementia, Alzheimer's and Parkinson's disease are representative degenerative diseases that show significant reduction in learning and memory. The mitochondrial proliferating agent of the present invention not only contributes to memory enhancement, therefore, but can also be developed as a therapeutic agent for Alzheimer's and Parkinson's disease.

Synthetic PPAR? Binders developed so far have less selectivity compared to other PPAR? And PPAR? Binders. The early selective ligand was L-631033, developed by Merk {J. SteroidBiochem. Mol. Biol. 1997, 63, p. 1-8), which was produced by introducing a functional group that is capable of fixing side chain based on its natural fatty acid morphology. The same research team later reported the most effective ligand L-165041 {J. Med. Chem. 1996, 39, p. 2629-2654), in which the compound known as the leukotriene agonist is functioning to activate human PPARÎ ±. This compound exhibited high selectivity for hPPARÔ, which is ten times the selectivity for PPARα or PPARγ. The EC 50 of the compound was 530 nM. Other ligands L-796449 and L-783483 have enhanced affinity (EC50 7.9 nM), but have poor selectivity for other hPPAR subtypes.

Glaxo-Smith-Kline reported GW2433 {Chem. Biol. 1997, 4, p.

909-918), the PPARÎ ± activator, which is a Y-type binder having a structure similar to the crystal structure of the PPARÂ binder pocket. Unlike conventional binders known hitherto, this binder has a benzene ring-containing Y-type structure, which favors spatial union to the 25 PPPRO binder pocket. This ligand is, however, a double active ligand that also has activity for hPPARa, suggesting that PPAR6 selectivity is reduced. PPAR? GW501516 ([2-methyl-4 - [[[4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl] methyl] sulfanyl] phenoxy] acetic acid binder ), recently developed by GlaxoSmithKline, exhibits much better physiological effect than any other previously developed ligand {Proc. Natl. Acad. Know. U.S.A. 2001, 98, p. 5306-5311).

OH

GW501516

The GW501516 has excellent affinity (1 to 10 nM) for PPARô and

Also excellent selectivity for PPARa or PPARy, which is at least a thousand times the selectivity of previous ligands.

so far, however, only 30 to 40% of the total binder joining pockets have resulted.

WO 2001/00603, filed by the Glaxo group, describes compound 10 represented by formula A below which contains GW501516 as a selective PPARα activator. This descriptive report includes, however, only a portion of the GW501516 test results using the Rhesus model.

CH 2 CH 3).

The thiazole compound represented by formula B as a selective PPARα activator was described in WO 2002/62774 deposited by the Glaxo group.

formula B

WO 2003/072100, filed by Eli Lilly, discloses a pharmaceutical composition for selective regulation of PPAR6 containing the compound represented by the following formula C.

PPAR? Activity induced by all ligands developed

R1

formula A

(where R5 is CF3 or F, R ”is H, CH3 or Cl and R '” is H, CH3 or sm F3C

, 0

OH

formula C

Technique Problem

The descriptive report only states, however, that the composition was

prepared and which is produced in the form of racemate, not as an optical isomer which

mass spectrometry of the racemate produced, which is confirmed by means of

PPAR? selectivity among racemic compounds of the thiazole derivative described in WO 2003/072100. The object of the present invention is therefore to provide the opioactive compound having high PPAR? Selectivity and a pharmaceutical composition, a functional cosmetic composition and a healthy food and animal feed composition containing the thiazole derivative opioactive compound. Description of the Invention

The present invention relates to the thiazole compound represented by Formula 1 as a PPARα (Peroxisome Proliferator Activated Receptor) ligand which can be used for the treatment of obesity, hyperlipidemia, arteriosclerosis, diabetes, dementia, Alzheimer's disease and Parkinson's and for muscle strengthening or memory enhancement and a pharmaceutical composition, cosmetic composition, healthy food composition and animal feed containing it.

[Formula 1]

comprises two types. The document only describes M ++ 1 value of

NMR H e acts as a selective PPAR? Activator, but does not mention the pharmacological effect as a selective PPAR? Activator.

Technical Solution

10

The present inventors have prepared an opioactive compound which has

WO 2003/072100 describes the thiazole compound represented by Formula C. The document only describes, however, M + +1 spectrometry value.

as a selective PPAR? activator, but does not mention the pharmacological effect as a selective PPAR? activator.

As represented by Formula 1, the active optical isomer of the racemic compound of Formula C has high selective activity for PPARô, but the S-isomer represented by Formula 2 exhibits significantly reduced activity for

Accordingly, the compound of Formula 1 according to the present invention is considered a selective invention of WO 2003/072100.

The compound represented by Formula 1 of the present invention may be prepared by the following reaction formula 1:

Reaction Formula 1

mass of the racemate produced, which is confirmed by NMR 1FI and acts

formula C

The compound of formula C above contains a chiral carbon and therefore there are stereoisomers thereof.

The present invention has confirmed that the R-isomer

PPARÔ.

[Formula 2]

15, // W [process Α-2] χι _ (/ γ OMgX ----------- · ► '■ - ('

4

THE

[process Α-1]

// \\

OH

Li -> - OMgX1 5

[process Α]

[process Α-4]

= \ / sV ^ X3 Ν "

ρ3 ° Λ /) ~ ^ - L

y

F3CWT ^ S ^ 0H

[process Β]

[process C]

10

Λ //

S ^> 0R1

[process E]

[process F]

The [process G] / ^ X / S

OH

13

(wherein R is a phenol protecting group which may be lower C1 -C4 alkyl, allyl, alkylsilyl, alkylarylsilyl or tetrahydropyranyl; R2 is a carboxylic acid protecting group containing C1 -C4 alkyl or allyl; X1 is a carbon atom.

2 3

bromine or iodine atom; X and X are independently a chlorine atom, bromine atom, iodine atom or residual group having nucleophilic substituted reactivity). The method of preparation according to the present invention is described in detail below. The following descriptions may not, however, limit the scope or spirit of the present invention.

Process A - Preparation of the compound represented by the formula 8 To prepare the compound represented by the formula 8,4-halo-2-

Methylphenol, the compound represented by Formula 3, was treated with Grignard reagent to protect the phenol group without an independent separation process, reacted with an organic and S step metal reagent and finally reacted with the compound represented by Formula 7. This process It has four steps of io subreation performed in sequence.

The subreaction steps are described in detail below.

Process A-1: The anhydride solvent used in this process is selected from the group consisting of isolated solvents such as diethyl ether, tetrahydrofuran, hexane and heptane, and mixed solvents comprising at least two of these solvents. It is more preferably to select diethyl ether, tetrahydrofuran or the mixed solvent comprising diethyl ether and tetrahydrofuran as the anhydrous solvent.

The Grignard reagent used herein may be selected from the group consisting of methyl, ethyl, r-propyl, w-propyl, β-butyl, seobutylmagnesium chloride (R2MgCl) and alkylmagnesium bromide (R2MgBr). Of these, wo-propylmagnesium chloride ((CI13) 2 CHMgCl) is preferably higher.

The reaction temperature is solvent dependent but is generally defined at -20 to 40 ° C and preferably at 0 ° C to room temperature (25 ° C). The reaction time depends on the reaction temperature and a solvent, but is generally from ten to sixty minutes and preferably from ten to thirty minutes.

Process A-2 and Process A-3: The organic metal reagent used for lithium halogen substitution may be selected from the group consisting of n-butyl lithium, sec-butyl lithium and tert-butyl lithium. Of these compounds, tert-butyl lithium is preferably higher. S is preferred with fine particles, which are added directly to

a solvent.

The reaction temperature depends on a solvent, but is generally set at -78 to 25 ° C. The reaction temperature for halogen and metal substitution is preferably -75 ° C and the temperature for introducing S is -75 ° C at room temperature (25 ° C). The halogen and metal substitution reaction takes ten to thirty minutes and the introduction reaction of S takes thirty to ninety minutes.

Process A-4: 5-Halogen methyl-4-methyl-2 [4-

(trifluoromethyl) phenyl] thiazole, the compound represented by Formula 7 used in this process, was prepared by the known method (WO 03/106442). The halogen of the compound represented by Formula 7 is selected from the group consisting of chlorine, bromine and iodine. Among these, chlorine is preferably higher.

The reaction temperature depends on a solvent, but is generally defined at -78 to 25 ° C and preferably at 100 ° C. The reaction time is generally from ten to 120 minutes and preferably from ten to sixty minutes.

Process B - Preparation of the compound represented by Formula 9

To prepare the compound represented by Formula 9, the compound represented by Formula 8 is preferably reacted with the compound generally used as the phenol protecting group in the presence of base.

The polar aprotic solvent used in this process is selected from the group consisting of AyV-dimethylformamide, N 1 N -dimethylacetamide, dimethyl siloxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane. The ether of the present may be selected from the group consisting of tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. Aromatic hydrocarbon is exemplified by benzene, toluene and xylene. As a solvent of the present, the polar aprotic solvent is preferred and particularly preferably N, N-dimethylformamide, chloroform or dichloromethane. The base of the present is amine, including pyridine, triethylamine, imidazole and N, Af-dimethylaminopyridine. For the alkyl or allyl etherified protecting group reaction, bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are used. Particularly, they are more preferably imidazole and potassium carbonate.

Alkylsilyl halide or alkylaryl silyl halide is used as the silyl protecting group and 3,4-dihydro-2 H -pyran is used as the tetrahydropyranyl protecting group.

The reaction temperature is solvent dependent but is generally defined at -10 to 80 ° C and more preferably at 0 ° C to room temperature (25 ° C). The reaction time depends on the reaction temperature and a solvent, but usually takes from one hour to one day. Most preferably, the reaction is completed within four hours.

Process C - Preparation of the compound represented by Formula 10 To prepare the compound represented by Formula 10, proton α of

The thioether of the compound represented by Formula 9 is treated with a strong alkali to generate a nucleophile, which reacts with various electrophiles.

The anhydride solvent used in this process is selected from the group consisting of isolated solvents such as diethyl ether, tetrahydrofuran, hexane and heptane, and mixed solvents comprising at least two of these solvents. It is most preferably selecting diethyl ether, tetrahydrofuran or the mixed solvent comprising diethyl ether and tetrahydrofuran as the anhydrous solvent.

The strong alkali used for proton extraction α is selected from the group consisting of potassium tert-butoxide (t-BuOK), lithium diisopropyl amide (LDA), 'butyl lithium, sec-butyl lithium and tert-butyl lithium and among these compounds lithium diisopropyl amide (LDA) is preferably higher.

The electrophile reacted with the thioether nucleophile is benzyl halide.

The reaction temperature depends on a solvent, but is generally from -78 to 25 ° C. Most preferably, the proton extraction reaction α is present in the presence of a strong alkali at -75 ° C, in which an electrophile is added. Then the temperature is slowly raised to room temperature (25 ° C). The reaction time differs between each reaction step. Extraction of protons α by a strong alkali takes, for example, from ten to thirty minutes and reaction with electrophile takes from thirty to ninety minutes.

Process D - Preparation of the compound represented by Formula 11

The compound represented by Formula 11 is obtained by eliminating the phenol protecting group from the compound represented by Formula 10.

The polar solvent used in this process is selected from the group consisting of Î ± V-dimethylformamide, Î ”V-dimethylacetamide, dimethyl siloxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane. The ether of the present may be selected from the group consisting of tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. The alcohol may be methanol or ethanol. The aromatic hydrocarbon is exemplified by benzene, toluene and xylene. As a solvent of the present, the polar solvent is preferred and particularly preferably tetrahydrofuran.

To eliminate the phenol protecting group, particularly to eliminate methyl, ethyl, tert-butyl, benzyl or allyl protecting group, trimethylsilyl iodide, ethanethioic alcohol sodium salt, lithium iodide, aluminum halide, boron or Lewis acid such as trifluoroacetic acid and, to eliminate the silyl protecting group such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl and tert-butyldimethyllyl, fluoride such as tetrabutylamoniofluor (Bu4N + F '), halogen acid ( hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid) or potassium fluoride. The use of fluoride is preferred to eliminate the silyl protecting group and more preferably tetrabutylammonium fluoride is used.

The reaction temperature depends on a method and a solvent, but is generally from 0 to 120 ° C and preferably from 10 to 25 ° C. The reaction time depends on the reaction temperature, but usually takes from thirty minutes to one day. Most preferably, the reaction is completed within two hours.

Process E - Preparation of the compound represented by Formula 12 The compound is prepared by separating the R isomer represented by Formula 12 and another S isomer from the racemic compound of Formula 11. This separation is performed by HPLC using a column. of normal chiral phase. At this time, the solvent is the mixed solvent comprising nonpolar solvents such as hexane, heptane and pentane, and polar solvents such as ethanol and isopropyl alcohol.

Process F - Preparation of the compound represented by Formula 13

To prepare the compound represented by Formula 13, the compound represented by Formula 12 is preferably reacted with halo-alkyl acetate or halo-allyl ester in the presence of base.

Alkyl haloacetate ester or allyl haloacetate ester is the general compound which can be readily obtained. Halogen at present is exemplified by chlorine atom, bromine atom and iodine atom. Preferably, bromoacetate methyl ester, bromoacetate allyl ester or bromoacetate ethyl ester is used as the alkyl halogenacetate ester or allyl halogenioacetate ester.

The solvent used in this process may be a single soluble solvent selected from the group consisting of Af, Af-dimethylformamide, NN-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol and methanol, or a solvent mixture prepared by mixing these solvents with 1 to 10% water. Preferably the higher solvent is a solvent mixture prepared by mixing acetone or dimethyl sulfoxide with 1 to 5% water.

The base used in this process is not limited as long as it has no bad influence on the reaction, whether strong or weak, as exemplified by alkali metal hydride, such as sodium hydride and lithium hydride, alkaline earth metal hydride. such as potassium hydride, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide and alkali metal carbonate such as lithium carbonate, potassium carbonate, potassium bicarbonate and cesium carbonate. Among these compounds, alkali metal carbonate is preferred and potassium carbonate is most preferably.

The reaction temperature is not limited, but is up to the boiling point of a solvent. High temperature is not preferred, however, to inhibit side reactions. The preferred reaction temperature is 0 to 60 ° C. The reaction time depends on the reaction temperature, but is usually thirty minutes to one day and preferably thirty to ninety minutes.

Process G - Preparation of the compound represented by Formula 1

The compound represented by Formula 1 is prepared from the compound represented by Formula 13 by hydrolyzing the carboxylic acid ester of the compound in the mixed solution of soluble inorganic salt and alcohol or salts are prepared from allyl ester in the presence of a palladium catalyst.

The solvent used in this process is a soluble solvent that can be mixed with water, such as alcohol, such as methanol and ethanol. The inorganic salt 15 used in this process is an aqueous solution prepared by the mixture of alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, with water in the concentration of 0.1 to 3 N, considering the type of alkali carboxylic acid salt. The acid used to obtain the compound represented by formula 13 as a carboxylic acid form is preferably an aqueous acetic acid solution or an aqueous solution of 0.1 to

3 N hydrochloric acid.

The reaction is preferably performed under low temperature in order to inhibit side reactions, which is generally 0 ° C at room temperature. The reaction time depends on the reaction temperature, but is usually from ten minutes to three hours and more preferably from thirty minutes to one hour.

The pharmaceutically acceptable salt of the compound represented by Formula 1 is prepared by substitution with allyl ester salt of the compound represented by Formula 13 using palladium tetrakistriphenylphosphine catalyst and metal salt according to reaction formula 2. The solvent used in this process is selected from from the group consisting of chloroform, carbon tetrachloride, dichloromethane, tetrahydrofuran and ethyl acetate. The catalyst used in this process is palladium tetrakistriphenylphosphine. The salt for salt substitution is potassium 2-ethyl hexanoate or sodium 2-ethyl hexanoate.

its solvates and salts, which can be efficiently used as a Peroxisome Proliferator Activated Receptor Activating Composition (PPAR?). Precisely, the compound represented by Formula 1 according to the present invention and pharmaceutically acceptable salts thereof can be very effective as a pharmaceutical composition for the treatment and prevention of arteriosclerosis or hyperlipidemia; for increased high density lipoprotein (HDL); for the treatment and prevention of diabetes; for the treatment and prevention of obesity; for muscle strengthening or increased resistance; for memory improvement; for the treatment and prevention of dementia or Parkinson's disease; and a composition for healthy food supplements, healthy drinks, food additives and animal feed. The compound represented by formula 1 or pharmaceutically acceptable salts thereof according to the present invention may be used for the functional cosmetic composition for the prevention and amelioration of obesity and for the functional cosmetic composition, for muscle strengthening and increased resistance. The functional cosmetic composition for strengthening muscles and increasing endurance may be formulated as an ointment, lotion, cream or gel to be applied to the body part before or after exercise and may be used over the long term to cause the desired effect. The compound represented by formula 1 or pharmaceutically acceptable salts thereof according to the present invention may be formulated as an ointment and applied

Reaction Formula 2

5th

The resulting S-containing compound represented by Formula 1 is a very important material as a PPAR? Protein binder.

The present invention includes the compound represented by Formula 1, on the body part for preventing or treating diabetes or diabetic foot ulcer, called diabetic ulcer.

The present invention also provides a peroxisome proliferator activated receptor (PPAR) activating composition containing the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as an active ingredient.

The pharmaceutically acceptable salt of the present includes all salts which are capable of forming carboxylic acid salts of the compound of formula 1 and alkali metal ions and alkaline earth metal ions, which are exemplified by Li +, Na +, K +, Ca2 + etc.

The effective dose of the compound represented by formula 1 or pharmaceutically acceptable salts thereof according to the present invention may be determined according to the type of compound, method of administration, target object and target disease, but is determined based on conventional medical standard. . The preferred dose of the compound represented by formula 1 is 1 to 100 mg / kg (body weight) / day. The frequency of administration may be one or several times daily within the permitted daily dosage. The composition according to the present invention may be administered orally or parenterally and may be used in general forms of pharmaceutical formulation. The composition according to the present invention may be formulated, for example, as tablets, powders, dry syrups, chewable tablets, granules, capsules, soft capsules, pills, beverages, sublinguals, etc. The tablets according to the present invention may be administered to patients by a method or route that provides the effective dose of the bioavailable tablet, which is the oral route. In addition, the method or route of administration may be determined according to the characteristics, stages of the target disease and other conditions. When the composition according to the present invention is formed as tablets, it may additionally include one or more pharmaceutically acceptable excipients. The content and characteristics of the excipient may be determined by the solubility and chemical properties of the selected tablet, route of administration and standard pharmaceutical practice. The compound of Formula 1 according to the present invention may be added to healthy food supplements or healthy drinks for the prevention or amelioration of hyperlipidemia; for increased high density lipoprotein (HDL); for the prevention and improvement of diabetes; for the prevention and improvement of obesity; for muscle strengthening or increased resistance; for memory improvement; for the prevention and amelioration of dementia or Parkinson's disease. At this point, the content of the compound in healthy foods and beverages can be adjusted according to purpose and application. In addition to the ingredients mentioned above, the compound represented by Formula 1 of the present invention may include a number of nutrients, vitamins, minerals (electrolytes), flavors including natural and synthetic flavors, coloring agents and extenders (cheese, chocolate etc.), pectic acid and its salts, alginic acid and its salts, organic acid, protective colloidal viscosity amplifiers, pH regulators, stabilizers, antiseptics, glycerin, alcohols, carbonators which are used for addition to soda etc.

Best form

Practical and currently preferred embodiments of the present invention are illustrated as shown in the following Examples.

It will be appreciated, however, that those skilled in the art, upon consideration of this specification, may make modifications and improvements within the spirit and scope of the present invention.

Example 1 - Preparation of the compound of Formula 8 (Process A)

500 mg (2.14 mmol) of 4-iodo-2-methylphenol was dissolved in 20 mL of anhydrous tetrahydrofuran in the presence of nitrogen and at that time the temperature was maintained at 0 ° C. 1.1 ml of isopropylmagnesium chloride (2M ether solution, 2.16 mmol) was slowly added, followed by reaction for ten minutes. The reaction solution was cooled to -78 ° C, when 2.77 ml of tert-butyl lithium (1.7 M, heptane solution, 4.70 mmol) was slowly added. After reaction for twenty minutes, 69 mg of S (2.14 30 mmol) was slowly added, followed by further reaction until the reagent temperature reached 15 ° C. Forty minutes later, 624 mg (2.14 mmol) of 5-chloromethyl-4-methyl-2 - [(4-trifluoromethyl) phenyl] thiazole represented by Formula 7 was dissolved in 2 mL of anhydrous THF, which was added. slowly at the same temperature. After an additional hour of reaction, the reaction was terminated by the addition of 20 ml of ammonium chloride solution 5. The organic layer was separated and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1, v / v) to give 78 mg (yield: 86%) of the target compound.

1H NMR (300 MHz, CDCl3) δ 7.96 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J

= 8.3 Hz), 7.19 (d, 1H, J = 1.5 Hz), 7.01 (dd, 1H, J = 8.2, 2.0 Hz), 6.62 (d, 1H , J =

8.2 lz), 5.86 (brs, 1H), 4.07 (s, 2H), 2.19 (s, 3H), 2.12 (s, 3H).

13 C NMR (75.5 MHz, CDCl 3) δ 163.9, 155.5, 151.7, 137.4, 136.9,

133.5, 131.9 (q, J = 32.6 Hz), 131.7, 126.8, 126.3, (q, J = 3.9 Hz), 125.8, 123.8, 115 , 7,33,2,16,2,14,8.

Example 2 - Preparation of the compound of Formula 9 (R1 = I-BufCH2 Si, Process B) 500 mg (1.26 mmol) of compound 8 and 171 mg (2.52 mmol) of imidazole were completely dissolved in 5 ml of dimethylformamide. 209 mg (1.38 mmol) of tert-butyldimethylsilyl chloride was added slowly, followed by stirring at room temperature for four hours. At the end of the reaction, the organic solvent was extracted using ammonium chloride and ethyl acetate solution. The moisture of the organic layer was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1, v / v) to give 610 mg (yield: 95%) of the target compound.

1H NMR (300 MHz, CDCl3): 7.97 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J =

8.2 Hz), 7.19 (d, 1H, J = 1.9 Hz) 7.07 (m, 1H), 6.69 (d, 1H, J = 8.3 Hz), 4.11 (s, 2H), 2.21 (s, 3H), 2.11 (s, 3H), 1.01 (s, 9H), 0.21 (s, 6H), 13 C NMR (75.5 MHz, CDCl 3): δ 163.2, 154.7, 151.5, 137.1, 136.6, 133.3, 132.4, 131.7, 131.2, 131.0, 130.2, 129.2, 126 , 6, 126.1, 126.06, 126.01, 125.9, 124.9, 119.4, 32.8, 25.9, 18.5, 16.9, 15.0, -4, 0

Example 3 - Preparation of the compound of Formula 10 (R Processo t-Bu BuCHCH Processo Processo Processo)

Q

300 mg (0.59 mmol) of the compound (R1 = I-Bu (CH3) 2-) of Formula 9

Preparations in Example 2 were dissolved in 5 ml of anhydrous tetrahydrofuran in the presence of nitrogen and the temperature was reduced to -78 ° C. 619 μΐ (2.0 M, ether solution, 1.24 mmol) of lithium diisopropyl amide was slowly added, followed by reaction for ten minutes. Then, 77 μΐ (0.65 mmol) of benzyl bromide was added to the reaction solution, followed by stirring for 30 minutes at the same temperature (-78 ° C). The reaction was terminated by the addition of 5 ml of ammonium chloride solution. The moisture of the organic layer was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1, v / v) to give 265 mg (yield: 75% ) of the target compound.

1H NMR (300 MHz, CDCl3): δ 7.97 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.03-7.26 (m 6.63 (d, 1H, J = 8.3 Hz), 4.51 (dd, 1H, J = 9.8, 5.3 Hz), 3.37 (dd, 1H, J = 9 , 8.3 Hz), 3.05 (dd, 1H, J = 13.6, 9.9 I did), 2.10 (s, 3H), 1.83 (s, 3H), 0.98 (s, 9H), 0.18 (s, 6H). 13 C NMR (75 MHz, CDCl 3): δ 163.5, 155.1, 151.8,

138.4, 137.7, 136.5, 133.5, 130.3, 129.3, 128.9, 127.2, 126.8, 126.7, 126.2, 126.1,

124.5, 119.4,49,2,44,4,26,1, 18.7, 17.1, 15.1, -3.81, -3.84.

Example 4 - Preparation of the compound of Formula 11 (Process D)

200 mg (0.33 mmol) of the compound (R1 = I-Bu (CH3) 2 Si) of Formula 10 prepared in Example 3 was dissolved in 5 ml of anhydrous tetrahydrofuran in the presence of nitrogen. 660 μΐ (0.66 mmol) tetrabutylammonium fluoride solution

1 M in tetrahydrofuran were slowly added at room temperature, followed by stirring for one hour. At the end of the reaction, the organic layer was separated by the addition of ethyl acetate and water. The moisture of the organic layer was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1, v / v) to give 146 mg (yield: 91%) of the target compound.

1H NMR (500 MHz, CDCl3): δ 7.92 (d, 2H, J = 8.2 Hz), 7.50 (s, 1H), 7.59 (d, 2H, J = 8.2 Hz), 7.07-7.22 (m, 6H), 6.85 (m, 1H), 6.44 (d, 1H, J = 8.2 Hz), 4.47 (dd, 1H, J = 9, 7.5 Hz), 3.39 (dd, 1H, J = 13.8, 5.4 Hz), 3.06 (dd, 1H, J =

13.8, 9.8 Hz), 2.12 (s, 3H), 1.73 (s, 3H). 13 C NMR (125 MHz, CDCl 3): δ 164.1,

155.7, 151.2, 138.0, 137.9, 137.0, 136.4, 133.8, 131.8, 131.5, 129.0, 128.6, 127.2,

127.0, 126.6, 126.14, 126.11, 125.7, 125.0, 122.9, 122.7, 115.2, 60.8, 49.1, 43.7, 21, 2, 15.9, 14.3, 14.2.

Example 5 - Preparation of the compound of Formula 12 (Process E)

90 mg of the compound of Formula 11 prepared in Example 4 was followed by a semi-prepared chiral HPLC column (Chiralpack AD-H) to generate 45 mg of the target compound represented by Formula 12 in R form and 45 mg of its corresponding S-form isomer.

Mobile phase: hexane / isopropyl alcohol: 90/10 Flow rate: 3 ml / min Example 6 - Preparation of the compound of Formula 13 (Process F)

20 mg (0.04 mmol) of the compound of Formula 12 prepared in Example 5 were thoroughly mixed with 10 mL of acetone containing 5% water and 127 mg (0.9 mmol, 2.3 equivalents) of potassium carbonate at room temperature. . 67 μΐ (0.6 mmol, 1.5 equivalents) of bromine acetate ethyl ester was added, followed by vigorous stirring for four hours. At the end of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate, which was dried over magnesium sulfate to remove moisture from the organic layer. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1, v / v) to give 22 mg (yield: 95%) of the target compound of Formula 13. 1H NMR (300 MHz5 CDCl3): 7.98 (d, 2Η, J = 8.1 Hz), 7.65 (d, 2H, J =

8.3 ΙΊζ), 7.06-7.27 (m, 7H), 6.55 (d, 1H, J = 8.4 Hz), 4.59 (s, 2H), 4.53 (dd, IH, J =

9.7, 5.3 Hz), 4.22 (q, 2H, J = 7.1 Hz), 3.37 (dd, 1H, J = 13.7, 5.3 Hz), 3.17 (m, 1H) 2.20 (s, 3H), 1.83 (s, 3H), 1.26 (t, 3H, J = 1.2 Hz). 13 C NMR (75 MHz, CDCl 3):

169.1, 163.6, 156.9, 151.8, 138.3, 137.4, 137.3, 136.4, 133.4, 129.3, 128.9, 128.6,

127.2, 126.8, 126.3, 126.2, 126.1, 125.1, 111.8, 65.9, 61.7, 49.1, 44.4, 16.5, 15.1,

14.5.

Example 7 - Preparation of the compound of Formula 1 (Process G)

20 mg (0.03 mmol) of the compound of Formula 13 prepared in Example 6 was thoroughly mixed with 15 mL of ethanol, to which 15 μΐ of 3 N sodium hydroxide solution was added. After stirring at room temperature for twenty minutes, the pH of the reaction mixture was adjusted to 2.0 by 2 N HCl. Vacuum distillation was performed to remove about 80% ethanol. The organic solvent was extracted using sodium chloride solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by LH-20 column chromatography to give 16 mg (yield: 98%) of the target compound of Formula 1.

1H NMR (500 MHz, CDCl3): δ 7.92 (d, 2H, J = 8.2 Hz), 7.50 (s, 1H), 7.59 (d, 2H, J = 8.2 Hz), 7.07-7.22 (m, 6H), 6.85 (m, 1H), 6.44 (d, 1H, J = 8.2 Hz), 4.47 (dd, 1H, J = 9, 7.5 Hz), 3.39 (dd, 1H, J = 13.8, 5.4 Hz), 3.06 (dd, 1H, J =

13.8, 9.8 Hz), 2.12 (s, 3H), 1.73 (s, 3H). 13 C NMR (125 MHz, CDCl 3): δ 164.1,

155.7, 151.2, 138.0, 137.9, 137.0, 136.4, 133.8, 131.8, 131.5, 129.0, 128.6, 127.2,

127.0, 126.6, 126.14, 126.11, 125.7, 125.0, 122.9, 122.7, 115.2, 60.8, 49.1, 43.7,

21.2, 15.9, 14.3, 14.2.

Experimental Example 1 - Activity and Cytotoxicity Test

The PPAR? Activities of the compound of form R represented by Formula 1 according to the present invention and the compound of form S represented by Formula 2 were measured by the transfection test. In addition, selectivity for PPAR, PPARa and PPARy subtypes was examined. Cytotoxicity was tested by MTT testing and toxicity and in vivo activity were screened by animal experimentation using mice.

Transfection test

CV-I cells were used in this test. Cells were inoculated into a 96-well plate containing DMEM supplemented with 10% FBS, DPS (with lipids removed) and 1% penicillin / streptomycin and cultured in a 5% CO2 incubator at 37 ° C. The experiment was performed according to the steps of inoculation, transfection, sample treatment and confirmation. Particularly, CV-I cells were inoculated into a 96-well plate (5000 cells / well), followed by transfection 24 hours later. Full length PPARs plasmid DNA, reporting DNA confirming PPARs activity due to their luciferase activity, β-galactosidase DNA providing information on transfection efficiency and transfection reagent were used for transfection. The compounds of Formula 1 and Formula 2 were dissolved in dimethyl sulfoxide (DMSO) and treated for cells by different concentrations. After culturing the cells in the incubator for 24 hours, the cells were lysed using lysis buffer. Luciferase activity and β-galactosidase activity were measured with a luminometer and a microplate reader. The luciferase values obtained were modified by the β-galactosidase values. These values were plotted and the EC50 was calculated. Table 1

compound ECsoinM) PPAR? PPAR? PPAR? (Inv. m ° formula 1 0.6 ia ia OH X) formula 2 5.1 ia ia OH As shown in Table 1, the compound represented by the formula

1 according to the present invention is highly selective for PPAR? The thiazole compound of Formula 1 according to the present invention demonstrated one hundred thousand fold higher selectivity to PPARα and PPARγ. EC50 of the PPARÎ ± Formula 1 compound was 0.6 nM and EC50 of the PPARÎ ± Formula 2 compound was 5.1 nM.

Isomer R, compound of Formula 1 according to the present invention, exhibited activity ten times stronger than isomer S, compound of Formula 2. The above results indicate that the compound of Formula 1 according to the present invention has high selectivity. . io MTT Test

The MTT test was performed to test the cytotoxicity of the compounds according to the present invention. MTT is a water-soluble yellow substance, but when it is introduced into a living cell, it becomes a purple insoluble crystal through dehydrogenase in mitochondria. Cytotoxicity can be confirmed by measuring OD550 after dissolution of MTT in dimethyl sulfoxide. The experiment was performed as follows.

CV-I cells were inoculated into a 96-well plate (5000 cells per well). Cells were cultured in a 5% CO 2 incubator at 37 ° C for 24 hours and treated with the compounds of Formula 1 and Formula 2 at different concentrations. Then the cells were cultured again by

24 hours, to which MTT reagent was added. After cultivation for fifteen minutes, the generated purple crystals were dissolved in dimethyl sulfoxide. Optical density was measured with a microplate reader to confirm cytotoxicity. As a result, it has been confirmed that the compound represented by Formula 1 of the present invention and the compound represented by Formula 2, its optical isomer, have no cytotoxicity, even at a concentration of one hundred thousand times the EC50 value.

Toxicity Test

Acute toxicity and reproductive toxicity tests were performed using mice to assess the toxicity of the compound according to the present invention. The compound of Formula 1 was orally administered to ICR mice after six weeks at a dosage of 50 mg / kg, 300 mg / kg and 2000 mg / kg, followed by fourteen days of toxicity observation. As a result, no deaths occurred according to the administration of the compound of Formula 1, 5 even at the highest concentration of 2000 mg / kg, and no significant changes in weight and food intake were observed either. Autopsy results showed no abnormal signs. The reproductive toxicity test result using C57BL / 6 mice was also consistent with the above, ie no toxicity caused by the compound of Formula 1 was observed. After oral administration of the compound to the pregnant mouse female, the gain was investigated. weight and the growth rate of the fetus. As a result, no significant differences were observed according to administration and no changes in bone development and disease-related issues.

Animal testing

Obesity inhibiting effect

An animal test using mice was performed to confirm the in vivo effect of the compound according to the present invention. C57BL / 6 mice (SLC Co.) were used at fourteen weeks. To induce obesity, feeds containing 35% fat were provided. In providing such high fat feeds for 35 days, vehicle GW501516 (10 mg / kg / day) and the compound of Formula 1 according to the present invention (10 mg / kg / day) were orally administered. As a result, only 26.5% of the GW501516-treated group and 23.1% of the compound-treated group according to the present invention exhibited weight gain compared with the vehicle-treated group (58.9%). , which increased by about 1A compared to the vehicle treated group. It has therefore been confirmed that the compound of Formula 1 according to the present invention has a strong obesity inhibiting effect, far more excellently than GW501516.

Diabetes Enhancing Effect GTT (glucose tolerance test) was performed to confirm the diabetes enhancing effect of the compound according to the present invention. Glucose (1.5 g / kg) was administered intra-abdominally to mice previously treated orally with samples for 78 days. Blood glucose was measured hourly. The fasting blood glucose level was lower in the group treated with the compound of the present invention than in the vehicle or GW501516 group. The group treated with the compound of the present invention exhibited rapid reduction in blood glucose in twenty to forty minutes and glucose release in one hundred minutes. In the meantime, the blood glucose level was not recovered to normal in the vehicle treated group even after 120 minutes. The GW501516-treated group exhibited lower blood glucose levels than the vehicle-treated group, but the blood glucose level did not recover to normal. The above results indicate that the compound of Formula 1 according to the present invention had excellent diabetes improving effect.

Improvement effect of hyperlipidemia

An in vivo animal test using six week C57BL / 6 mice (SLC Co.) was performed to confirm the ameliorating effect of the hyperlipidemia of the compound according to the present invention. Animals 20 received oral administration of 10 mg / kg / day of the compound of Formula 1 according to the present invention and GW501516 by feeding on high fat diets. Six weeks later, blood was taken from the orbital veins. Serum was separated and blood HDL level was measured by a biochemical method. As a result, the HDL level increased by 36.3% in the GW501516 treated group compared to the control. The FIDL level increased by 44.6% in the group treated with the compound of Formula 1 according to the present invention. The above results indicate that the compound of Formula 1 according to the present invention increases blood HDL more efficiently than GW501516.

Arteriosclerosis inhibitory effect In vivo animal testing was performed using ApoE- / - mice, which is an animal model for arteriosclerosis, to confirm the atherosclerosis inhibitory effect of the compound according to the present invention. The animals received oral administration of 2 mg / kg / day of the compound of Formula 1 according to the present invention by feeding on high fat and high cholesterol diets (20% fat, 1.25% cholesterol). diet AIN-93G). Twenty-eight days later plaque staining was performed throughout the artery using Sudan IV to investigate the inhibitory effect of compound atherosclerosis by comparing the results between experimental and control groups. As a result, 30% of atherosclerosis was inhibited in ApoE - / - mice treated with the compound of Formula 1 according to the present invention as compared to the control.

Enhancing effect of muscle function and strengthening muscle endurance.

An animal test was performed to confirm the strengthening of the

muscular endurance and the enhancing effect of muscle function of the composition according to the present invention. Most muscles are generated at the developmental stage. Thus, the compound of Formula 1 (10 mg / kg / day) was orally administered to pregnant mouse females during pregnancy or lactation or both pregnancy and lactation. Weight gain and growth rate were not much different between the control and treatment groups. Muscles were observed after skin removal. As a result, the muscles in the treatment group were red, as opposed to control. ATPase spots and immunoblots were performed. As a result, 25 type I muscle fiber increased in the group treated with the Formula I compound. The effect of muscle fiber changes on endurance and muscle function improvement was investigated using the treadmill test. As a result, driving time was much longer in the group treated with the compound of Formula 1.

Table 2 - Results of the muscle endurance test

Rate of increase (group in pregnancy lactation pregnancy + lactation treatment / group time length long time length control long) group of 2.3 2.4 2.1 2.2 2.9 times 3.0 times treatment times times times times By administering the compound of the present invention to adults, muscle endurance and muscle function have also been improved. Particularly, the compound of Formula 1 was orally administered to 5 C57BL / 6 mice after ten weeks at a concentration of 10 mg / kg during which time mice were forced to exercise. The exercise was performed on a treadmill for 30 minutes once a day for 30 days at precisely 2 m / min for the first five minutes, 5 m / min for five minutes, 8 m / min for five minutes and 20 m / min. for the last five minutes. In the end, the effect of improving muscle endurance and muscle function was tested using a treadmill. As a result, exercise time (1.5 times) and exercise distance (1.6 times) were all increased in the group treated with the compound of the present invention compared to the control.

Memory Enhancement An animal test was performed to investigate the therapeutic effect.

of the compound of the present invention on dementia and Parkinson's disease based on its memory enhancing effect. To confirm the effect of the compound of the present invention on the brain developmental period, the compound was administered orally to pregnant mouse females at a concentration of 10 mg / kg during pregnancy and lactation. The Morris pool test was performed to detect any change in brain function in the treatment group and the control group. As a result, the average time taken to find the platform was much shorter in the Formula 1 compound treated group compared to the control group; precisely, the treatment group spent 6.8 seconds finding the platform and the control group spent an average of 24.2 seconds, suggesting that the Formula 1 compound had an excellent memory enhancing effect.

The therapeutic effect of the compound of the present invention on dementia and Parkinson's disease based on its memory enhancing effect was investigated using an animal model of brain disease (ten week C57BL / 6 mice). First, LPS was injected into the brain of the mouse to construct an animal model of brain disease. The 5 mice were divided into four groups according to administration and exercise. The exercise was performed with a treadmill at a speed of 2 m / min for the first five minutes, 5 m / min for five minutes, 8 m / min for five minutes and 20 m / min for the last five minutes. At the end, the Morris pool test was performed. The results are summarized in Table 3. As a result, the therapeutic effect of the compound of Formula 1 according to the present invention on dementia and Parkinson's disease by compound memory enhancement and exercise was confirmed in the model. brain disease animal.

Table 3 - Pool Test Results

15

Performance group Pool test results control group Exercise (X) 36 seconds Exercise (O) 29 seconds treatment group Exercise (X) 25 seconds Exercise (O) 13 seconds Industrial application

The thiazole derivative compound according to the present invention as a PPAR? Binder, which has selective meanings from the above inventions, can be used efficiently as a pharmaceutical composition for the treatment and prevention of arteriosclerosis or hyperlipidemia; for increased high density lipoprotein (FIDL); for the treatment and prevention of diabetes; for the treatment and prevention of obesity; for muscle strengthening or increased resistance; for memory improvement; for the treatment and prevention of dementia or Parkinson's disease; and a composition for healthy food supplements, healthy drinks, food additives, functional cosmetics and animal feed.

Claims (16)

1. Thiazole compound characterized by Formula 1 or pharmaceutically acceptable salts thereof. [Formula 1] <formula> formula see original document page 29 </formula> Pharmaceutical composition for the prevention and treatment of atherosclerosis or hyperlipidemia characterized in that it contains the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Pharmaceutical composition for raising the level of high density lipoprotein (HDL) characterized in that it contains the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Pharmaceutical composition for the prevention and treatment of diabetes characterized in that it contains the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Pharmaceutical composition for the prevention and treatment of obesity characterized in that it contains the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Pharmaceutical muscle-building or resistance-enhancing pharmaceutical composition comprising the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Pharmaceutical composition for the improvement of memory or for the prevention and treatment of Alzheimer's or Parkinson's dementia or dementia characterized in that it contains the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Healthy food adjuvant or healthy drink characterized in that it contains the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Healthy food adjuvant or healthy drink according to claim 8 is characterized in that the healthy food adjuvant or healthy drink is used for the prevention and amelioration of atherosclerosis or hyperlipidemia; for increased high density lipoprotein (HDL); for the prevention and improvement of diabetes; for the prevention and improvement of obesity; for muscle strengthening or increased resistance; for memory improvement; and for the prevention and improvement of Alzheimer's or Parkinson's dementia or disease. Food additive characterized in that it contains the thiazole compound represented by Formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Food additive according to Claim 10, characterized in that the food additive is used for the prevention and amelioration of atherosclerosis or hyperlipidemia; for increased high density lipoprotein (HDL); for the prevention and improvement of diabetes; for the prevention and improvement of obesity; for muscle strengthening or increased resistance; for memory improvement; and for the prevention and improvement of Alzheimer's or Parkinson's dementia or disease. An animal feed composition comprising the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Animal feed composition according to claim 12, characterized in that the animal feed composition is used for the prevention and amelioration of atherosclerosis or hyperlipidemia; for increased high density lipoprotein (HDL); for the prevention and improvement of diabetes; for the prevention and improvement of obesity; for muscle strengthening or increased resistance; for memory improvement; and for the prevention and improvement of Alzheimer's or Parkinson's dementia or disease. Functional cosmetic composition comprising the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient. Functional cosmetic composition according to claim 14, characterized in that the functional cosmetic composition is used for the prevention and amelioration of obesity and for the strengthening of muscles and the increase of resistance. Activated receptor activating composition characterized by peroxisome proliferator δ (PPAR6) containing the thiazole compound represented by formula 1 or pharmaceutically acceptable salts thereof as defined in claim 1 as an active ingredient.